Over 90% of cancer mortality is directly associated with the systemic cancer cell metastasis to vital organs and no treatment option effectively prevents metastatic progression. Thus, for the 162,000 American women with metastatic breast cancer, their five-year survival rate is only 23%. The long-term objective of this research is to discover and develop new drugs that curb the metastatic spread of breast cancer. Target organassociated inoperable situations typically make small-molecule-based therapeutics the only viable option. Breast cancers can metastasize to multiple organs such as lung, bone, brain, and liver. Gene expression profiling studies of organotropic subclones derived from the triple-negative breast cancer (TNBC) cell line MDA-MB-231 led to the identification of signature gene profiles that predict metastatic potential in clinical samples. Built on the hypothesis that the combination of chemical diversity and effective bioassays will afford potential drug leads, these TNBC-derived organotropic subclones were used as in vitro models to evaluate compounds for antimetastatic activities. Our preliminary data support this hypothesis by demonstrating that compounds that disrupt tumor metabolism specifically suppress target organ-dependent organotropic metastatic breast cancer cells. This research expands and validates our initial compound evaluation efforts with approved oncology drugs, structurally and mechanistically diverse chemicals that include natural products, and herbal medicine-derived phytochemical sets (Aim 1). The results from this Aim will further validate this conceptually novel drug discovery platform, generate drug leads, and yield potential non-cytotoxic chemopreventive antimetastatic phytochemicals that can be rapidly forwarded to preclinical evaluation. The target organ selectivity displayed by mitochondrial disruptors prompted initial comparative studies of tumor bioenergetics among organotropic TNBC cell lines. Based on our observations, we propose a potentially targetable ?metabolic plasticity? model for organotropic metastasis. Specifically, metastatic cancer cells are metabolically pluripotent and assume the metabolic form that is most suitable for outgrowth in the parenchyma of target organs. To test this hypothesis, comparative metabolic flux studies will be performed in organotropic cell lines (Aim 2). The results from this Aim will provide experimental evidence to support our potentially groundbreaking theory of metastatic metabolic plasticity, and afford new metabolism-based targets for antimetastatic drug discovery. While initially identified mitochondria-targeted agents may not be suitable for drug development, the proposed pathway characterization, mechanistic, and compound evaluation studies are designed to discover leads with favorable druggability profiles. Pending future development, organ-selective antimetastatic agent combinations will enhance treatment outcomes and prolong survival in patients with metastatic cancers. In line with AREA program objectives, this project will strengthen the UM natural products and metabolism research environment and afford students hands-on antitumor drug discovery experience.